Subject Protection is Goal of Draft Guidance on Conflicts of Interest

Recent relative calm on the research scandal front has resulted in diminishing public focus on clinical research oversight and enforcement. The change is visible in a proposed guidance on Financial Relationships and Interests in Research Involving Human Subjects.¹ The guidance offers suggestions that research organizations identify and manage financial conflicts of interest, but fails to provide specific standards or requirements or to respond to calls for clear national guidelines.

The guidance applies to all research funded by the Department of Health and Human Services (HHS) or regulated by the Food and Drug Administration. It does not change current FDA requirements that sponsors document and disclose the financial interests of investigators. And it fails to reconcile confusing differences between HHS and FDA policies. Existing guidelines require that researchers funded by the National Institutes of Health (NIH) disclose financial interests over $10,000, while FDA requires that sponsors report financial arrangements with investigators over $25,000.

Instead, the draft guidance lists points that research organizations, IRBs, and investigators should consider when evaluating whether specific financial relationships create financial interests in research studies that may adversely affect the rights and welfare of subjects. Points to consider include:

• whether a financial relationship makes it inappropriate for an institution to conduct certain research.
• whether a conflict of interest (COI) can be managed by reducing the financial interest, disclosing the interest to prospective subjects, increasing oversight, or modifying the roles of particular researchers.
• the need for research organizations to establish COI committees to address financial interests.
• whether IRBs are following procedures to fully consider financial interests.
• whether to include information on financial interests in consent documents or to modify the consent process to reduce potential bias.

The advisory nature of the proposal aims to appease the academic research community, which objected strenuously to a draft interim guidance on managing COIs issued by the HHS Office of Human Research Protections (OHRP) in January 2001. Research organizations regarded that approach to addressing COIs as overly prescriptive and premature, while patient advocates protested that it did not go far enough to protect research participants.

Interested parties disputed whether IRBs were too overburdened to deal with financial conflicts, and asked if institutional COI committees were too biased. There was little agreement about what constituted a significant financial interest, who should review COI reports, whether reporting and disclosure should be mandatory, whether financial interests should be banned outright, and whether financial interests should be disclosed to potential research participants during the informed consent process.

The new draft guidance document fails to resolve these issues. It basically leaves it to research entities to determine whether a financial interest could affect research participants and, if so, how best to manage or eliminate it. FDA is accepting comments on the policy through 30 May 2003 and will review these opinions with OHRP and other HHS officials when crafting a final guidance.

Shift in FDA emphasis
Although the draft guidance does not alter FDA policies for reporting financial interests in new drug applications (NDAs), it reflects a change in the agencys approach to monitoring clinical research. FDA traditionally has reviewed selected clinical study reports filed with NDAs to verify the quality and integrity of study data. In the wake of scandals involving harm to trial participants in recent years, the agency increasingly is using its oversight authority to protect study participants. This has involved more audits of IRBs and of clinical sites while trials are going on, instead of just examining research reports and visiting sites later to ensure that investigators followed protocols and consent procedures.

Consequently, FDA BIMO (bioresearch monitoring) inspectors now are reviewing more IRBs and clinical sites in real time. The Division of Scientific Investigations (DSI) in the Center for Drug Evaluation and Research (CDER) is visiting about 150 IRBs each year, primarily those actively overseeing studies under investigational new drug applications.

Similarly, the Division of Bioresearch Monitoring in the Center for Devices and Radiological Health (CDRH) reviews about 100 IRBs annually to ensure appropriate oversight of studies for medical devices. CDRH also is auditing more trial sponsors to see that they are taking proper steps to monitor researchers and ensure the validity of data.